Field of the Invention
Metformin 2,4-dioxothiazolidin-3-ide(s), metformin salts of 2,4-thiazolidinedione, or metformin salts of rosiglitazone or pioglitazone are described for the treatment of diabetes mellitus Type2, gestational diabetes, coronary artery disease, polycystic ovary syndrome, premature puberty, non-alcoholic fatty liver disease, cancer such as pancreatic cancer, and other diseases which manifest insulin resistance.
Also, included are the prodrugs (N—((N—(N,N-dimethylcarbamimidoyl)carbamimidoyl)carbamoyl)-2-mercaptoacetamide) and N—((N—(N,N-dimethylcarbamimidoyl)carbamimidoyl)carbamoyl)-2-mercaptoacetamide•metformin.
Description of Related Art
Metformin as its hydrochloride salt is widely prescribed and is the drug of choice for the treatment of diabetes mellitus Type2 (T2D), characterized by insulin resistance, especially in overweight patients. Insulin resistance is the inability of the pancreas to produce sufficient insulin and/or muscle, fat, and liver cells to utilize available insulin for the uptake of glucose. Metformin is the only antidiabetic drug that has been conclusively shown to prevent the cardiovascular complications of diabetes. It helps reduce LDL cholesterol and triglyceride levels, and is not associated with weight gain. As of 2010, metformin is one of only two oral antidiabetics in the World Health Organization Model List of Essential Medicines (the other being glibenclamide) (Wikipedia).
Additionally, metformin is increasingly being used in polycystic ovary syndrome (PCOS), non-alcoholic fatty liver disease (NAFLD) and premature puberty; three other diseases that feature insulin resistance (Wikipedia).
Most common adverse effects of metformin hydrochloride is gastrointestinal upset, including diarrhea, cramps, nausea, vomiting and increased flatulence; possibly due to the high dose of 1-2.5 g/daily, and is usually managed by a starting low dose and building up to the maintenance dose, or through extended release formulations.
Organic acid salts of metformin have been prepared. For example U.S. Pat. No. 6,031,004 describes metformin salts of dibasic acids (2:1 molar ratio), metformin (2:1) fumarate, and metformin (2:1) succinate. Published EP 2303838A1 describes the 1:1 glycinate salt of metformin Published WO 2011025271A describes the preparation and formulations of metformin ascorbate. None of these products have yet reached the market.
2,4-Thiazolidinedione is an integral, covalently linked, structural moiety in a class of highly successful potent Type2 diabetes drugs known as the thiazolidinediones (TZDs). These TZDs act by activating PPARs (peroxisome proliferator-activated receptors), a group of nuclear receptors, with greatest specificity for PPARγ (gamma). The endogenous ligands for these receptors are free fatty acids (FFAs) and eicosanoids. When activated, the receptor binds to DNA in complex with the retinoid X receptor (RXR), another nuclear receptor, increasing transcription of a number of specific genes and decreasing transcription of others. Through a series of steps this leads to a decrease in insulin resistance, and improved lipid profile (Wikipedia). The best known therapeutic agents in the TZDs class are: rosiglitazone, (RS)-5-[4-(2-[methyl(pyridin-2-yl)amino]ethoxy)benzyl]thiazolidine-2,4-dione maleate (Avandia®, trademark of SmithKline Beecham), and pioglitazone, (RS)-5-(4-[2-(5-ethylpyridin-2-yl)ethoxy]benzyl)thiazolidine-2,4-dione hydrochloride (Actos®, trademark of Takeda Pharmaceutical Company). These are highly effective, low dose, insulin sensitizers that were approved by the FDA and market launched in the 1990s for treating T2D. Surprisingly, there appear to be no known mechanistic studies of the 2,4-thiazolidinedione moiety when used alone as a hypoglycemic agent, or its activity as a ligand binding at the PPARs (peroxisome proliferator-activated receptors).
The TZDs are generally prescribed in conjunction with metformin hydrochloride, either separately, or as an admixture in one pill. For example, Avandamet® is a combination therapy of rosiglitazone maleate and metformin hydrochloride (2-4 mg plus 500 mg, respectively; once or twice daily). Similarly, ActoPlus Met is a combination pill of pioglitazone hydrochloride and metformin hydrochloride (15 mg plus 500-850 mg, respectively; once or twice daily). A disadvantage of this therapy is that the adverse effects of metformin hydrochloride as gastrointestinal upset are still present.
Saxagliptin (Onglyza®, trademark of Astrazeneca AB), Sitagliptin (Januvia®, trademark of Merck & Co), and Alogliptin (Nesina®, trademark of Takeda Pharmaceutical Company Ltd) are antidiabetic drugs in a new class of dipeptidyl peptidase-4 (DPP-4) inhibitors. These are prescribed alone or in a combination with metformin hydrochloride, e.g., as Janumet®, trademark of Merck & Co. Other DPP-4 inhibitors are nearing FDA approval. Recently reported large clinical studies suggest that the gliptins, while they did not increase heart attack risk compared with a placebo, did not lower that risk. There was significantly more risk of heart failure and hospitalizations with one of the drugs (Wall Street Journal Sep. 3, 2013 B3). The clinical expert opinion is that lowering glucose level should be accompanied with improved cardiovascular health, such as by lowering of cholesterol and blood pressure.
Clearly, finding a drug that treats insulin resistant diseases, while having the needed safety for cardiovascular and gastrointestinal concerns, is still needed.